Vascular endothelial cells (EC) or endothelial progenitor cells (EPC) derived from stem cells could potentially lead to a variety of clinically relevant therapeutic applications, including various strategies for treating heart and vascular diseases. However, because EC exhibit a variety of functionally distinct subphenotypes, it is important to be able to generate the appropriate endothelial type. This study will explore the limits and importance of EC fate and generate methodologies for directing EC subphenotypes.

Statement of Benefit to California:

Vascular endothelial cells (EC) or endothelial progenitor cells (EPC) derived from stem cells could potentially lead to a variety of clinically relevant therapeutic applications, including various strategies for treating heart and vascular diseases. However, because EC exhibit a variety of functionally distinct subphenotypes, it is important to be able to generate the appropriate endothelial type. This study will explore the limits and importance of EC fate and generate methodologies for directing EC subphenotypes for treating these patients.

Review Summary:

This Exploratory Concepts Track application tests the hypothesis that human embryonic stem cells (hESCs) can be directly differentiated into the various functionally distinct endothelial cell (EC) subtypes using chemical and physical means. These vascular EC subtypes derived from hESCs have the potential to be utilized in therapeutic applications. To test this hypothesis, Aim 1 will elucidate how hESCs may differentiate into ECs necessary for blood vessel branching. Then, Aim 2 will study how hESCs differentiate into arterial ECs (Aim 2). In addition, Aim 2 will investigate the role mechanical shear stress in the specification of arterial vs. venous endothelial cells.
Significance and Innovation
- The proposal addresses significant issues in regenerative medicine, particularly the specification of endothelial cells that are differentiated from hESC.
- The mechanistic focus on subtype specification is important and significant.
- The ability to directly differentiate pure populations of functionally distinct EC that could be utilized to treat a wide range of diseases is highly novel and potentially transformative.
Feasibility and Experimental Design
- Reviewers praised the well-designed project with supportive preliminary data to investigate specification of hESC-derived EC into various subtypes.
- While the role of sheer stress in differentiation was deemed of potential importance in differentiation of EC, reviewers were not clear if experiments outlined would be successful. Thus, reviewers considered Aim 2 to be high risk.
- Reviewers suggested that the PI should consider in greater depth the potential complexity of producing EC subtypes and lack of alternative approaches if the differentiating factors that will be utilized are not effective.
Principal Investigator (PI) and Research Team
- PI is an Assistant Professor in Bioengineering and her laboratory has significant experience in differentiation of hESC.
- PI has good productivity.
- Description of research team is vague.
Responsiveness to the RFA
- The project is responsive to the RFA in that it uses hESCs to study endothelial subtype specification.